Mono(ADP-ribosyl)ation and poly(ADP-ribosyl)ation of proteins in developing liver and in hepatomas: relation of conjugate subfractions to metabolic competence and proliferation rates.

Abstract

Endogenous levels of mono(ADP-ribose)-protein conjugates are low in fetal liver. They increase during development reaching 30-times higher levels in the adult stage. Undifferentiated hepatomas also exhibit low degrees of mono(ADP-ribosyl)ation compared with differentiated tumors. The observed changes cannot be explained by depolymerisation of pre-existing protein-bound poly(ADP-ribose) groups or elongation of monomeric ADP-ribose residues since the monomeric and polymeric residues change independently, the absolute levels of residues present in the form of polymers being 20--350-times lower than monomeric ADP-ribose residues. Subfractionation of the mono(ADP-ribose)-protein conjugates on the basis of their NH2OH sensitivity also showed independent changes during liver development. The level of the NH2OH-sensitive conjugates exhibit an inverse relationship to cell proliferation rates in normal and malignant hepatic tissues, while the NH2OH-resistant subfraction, which was hardly detectable in fetal liver, could be related to the degree of terminal differentiation (relative to adult liver). The ratio of NH2OH-resistant to NH2OH-sensitive mono(ADP-ribose)-protein conjugates being near unity in adult liver, fell to extremely low values in fetal and neonatal liver. In undifferentiated hepatomas (proliferating or stationary), however, the ratio was higher than in the adult normal tissue. This parameter, then, allows one to discriminate between malignant and normal hepatic tissues with similar proliferative capacity and similar metabolic competence. On the basis of the findings presented it is suggested that covalent modification of proteins by mono(ADP-ribosyl)ation and poly(ADP-ribosyl)ation serve multiple and independent functions.